title: Genetic analysis of quantitative phenotypes in AD and MCI: imaging, cognition and biomarkers.
abstract: The Genetics Core of the Alzheimer's Disease Neuroimaging Initiative (ADNI), formally established in 2009, aims to provide resources and facilitate research related to genetic predictors of multidimensional Alzheimer's disease (AD)-related phenotypes. Here, we provide a systematic review of genetic studies published between 2009 and 2012 where either ADNI APOE genotype or genome-wide association study (GWAS) data were used. We review and synthesize ADNI genetic associations with disease status or quantitative disease endophenotypes including structural and functional neuroimaging, fluid biomarker assays, and cognitive performance. We also discuss the diverse analytical strategies used in these studies, including univariate and multivariate analysis, meta-analysis, pathway analysis, and interaction and network analysis. Finally, we perform pathway and network enrichment analyses of these ADNI genetic associations to highlight key mechanisms that may drive disease onset and trajectory. Major ADNI findings included all the top 10 AD genes and several of these (e.g., APOE, BIN1, CLU, CR1, and PICALM) were corroborated by ADNI imaging, fluid and cognitive phenotypes. ADNI imaging genetics studies discovered novel findings (e.g., FRMD6) that were later replicated on different data sets. Several other genes (e.g., APOC1, FTO, GRIN2B, MAGI2, and TOMM40) were associated with multiple ADNI phenotypes, warranting further investigation on other data sets. The broad availability and wide scope of ADNI genetic and phenotypic data has advanced our understanding of the genetic basis of AD and has nominated novel targets for future studies employing next-generation sequencing and convergent multi-omics approaches, and for clinical drug and biomarker development.
authors.affiliation: Center for Neuroimaging and Indiana Alzheimer's Disease Center, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, 355 W 16th Street, Suite 4100, Indianapolis, IN, 46202, USA, shenli@iu.edu.
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.forename: Paul M
authors.initials: PM
authors.lastname: Thompson
authors.forename: Steven G
authors.initials: SG
authors.lastname: Potkin
authors.forename: Lars
authors.initials: L
authors.lastname: Bertram
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Foroud
authors.forename: Robert C
authors.initials: RC
authors.lastname: Green
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Hu
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Huentelman
authors.forename: Sungeun
authors.initials: S
authors.lastname: Kim
authors.forename: John S K
authors.initials: JS
authors.lastname: Kauwe
authors.forename: Qingqin
authors.initials: Q
authors.lastname: Li
authors.forename: Enchi
authors.initials: E
authors.lastname: Liu
authors.forename: Fabio
authors.initials: F
authors.lastname: Macciardi
authors.forename: Jason H
authors.initials: JH
authors.lastname: Moore
authors.forename: Leanne
authors.initials: L
authors.lastname: Munsie
authors.forename: Kwangsik
authors.initials: K
authors.lastname: Nho
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Ramanan
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Risacher
authors.forename: David J
authors.initials: DJ
authors.lastname: Stone
authors.forename: Shanker
authors.initials: S
authors.lastname: Swaminathan
authors.forename: Arthur W
authors.initials: AW
authors.lastname: Toga
authors.forename: Michael W
authors.initials: MW
authors.lastname: Weiner
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Saykin
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000503:physiopathology* / Q000523:psychology; D015415:Biomarkers / Q000378:metabolism; D003071:Cognition / Q000502:physiology; D060825:Cognitive Dysfunction / Q000235:genetics* / Q000503:physiopathology* / Q000523:psychology; D006801:Humans; D059906:Neuroimaging / Q000379:methods; D010641:Phenotype
chemical_list: D015415:Biomarkers